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244 Cards in this Set
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1. Inhibitors of thymidylate synthase
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Thymidylate (dTMP) is synthesized by the methylation of 2'-deoxyuridylate (dUMP). This reaction, which is catalyzed by thymidylate synthase, requires MTHF as a cofactor.
Inhibitors of thymidylate synthase thereby decrease cellular availability of dTMP and cause "thymineless" cell death. |
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2. What are the three inhibitors of thymidylate synthase?
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1. Fluorouracil (5-FU)
2. Capecitabine 3. Pemetrexed |
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3. 5-Fluorouracil (5-FU)
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5-Fluorouracil inhibits DNA synthesis, primarily by interfering with the biosynthesisis of thymidylate. 5-FU is first converted to 5-fluoro-2'-deoxyuridylate (FdUMP) by the same pathways that convert uracil to dUMP. FdUMP then inhibits thymidylate synthase by forming, together with MTHF, a stable, covalent ternary enzyme-substrate-cofactor complex.
5-FU can also be metabolized to floxuridine triphosphate (FUTP), which can be incorporated into mRNA in place of uridylate and can thereby interfere with RNA processing. |
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4. Therapeutic uses of 5-FU
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5-FU is used as an antineoplastic agent, especially in the treatment of carcinomas of the breast and GI tract. 5-FU has also been used in the topical treatment of premalignant keratoses of the skin and of multiple superficial basal-cell carcinomas
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5. Serious adverse effects of 5-FU
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1. Coronary atherosclerosis
2. Thrombophlebitis 3. GI ulcer 4. Myelosuppression 5. Cerebellar syndrome 6. Visual changes 7. Stenosis of lacrimal system |
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6. Common adverse effects of 5-FU
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1. Alopecia
2. Rash 3. Pruritus 4. Photosensitivity 5. GI disturbance 6. Stomatitis 7. Headache |
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7. Contraindications of 5-FU
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1. Severe bone marrow depression
2. Poor nutritional state 3. Serious infection 4. Dihodropyrimidine dehydrogenase deficiency 5. Pregnancy |
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8. 5-FU therapeutic considerations
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5-FU is a uracil analogue, that, after intracellular modification, inhibits thymidylate synthase by binding to the deoxyuridylate (substrate) site on the enzyme.
In addition to inhibiting thymidylate synthase, 5-FU interferes with protein synthesisi after the drug metabolite FUTP is incorporated into mRNA. Folinic acid can be used to potentiate the action of 5-FU. |
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9. Capecitabine
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Capecitabine is an orally available prodrug of 5-FU. It is absorbed across the GI mucosa and converted by a series of three enzymatic reactions to 5-FU.
Capecitabine is approved for the treatment of metastatic colorectal cancer and as second line therapy in metastatic breast CA. |
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10. Contraindications and adverse effects of capecitabine
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Adverse effects same as for 5-FU
Dihodropyrimidine dehydrogenase deficiency and severe renal impairement are contraindications. |
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11. Pemetrexed
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Pemetrexed is a folate analogue that, similar to endogenous folate and the dihydrofolate reductase (DHFR) inhibitor methotrexate, is transported into cells by the reduced folate carrier and polyglutamated by the intracellular enzyme folylpolyglutamate synthase.
Polyglutamated pemetrexed is a potent inhibitor of thymidylate synthase and a much weaker inhibitor of DHFR. |
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12. Therapeutic uses for pemetrexed
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Approved as a single agent in the second-line treatment of nonsmall cell lung CA and in combination with cisplatin in the treatment of malignant pleural mesothelioma.
To reduce toxicity to normal cells, patients treated with pemetrexed are also given folic acid and vitamin B12 supplementation. |
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13. Serious adverse effects of pemetrexed
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1. Myelosuppression
2. Angina 3. MI 4. Stroke 5. Thrombophlebitis 6. Liver damage 7. Bullous skin rash |
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14. Common adverse effects of pemetrexed
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1. Fatigue
2. Nausea 3. Vomiting 4. Diarrhea 5. Stomatitis |
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15. Pemetrexed contraindications
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1. Hypersensitivity to pemetrexed
2. Severe renal impairment. |
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16. 5-FU vs. pemetrexed
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The 5-FU derivative 5-FdUMP inhibits thymidylate synthase by binding to the dUMP [substrate] on the enzyme, whereas pemetrexed inhibits thymidylate synthase by binding to the MTHF [cofactor] on the enzyme.
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17. Inhibitors of purine metabolism
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Drug metabolites inhibit IMPDH and other synthetic enzymes, thereby interfering with AMP and GMP synthesis.
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18. What are the inhibitors of purine metabolism?
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1. 6-Mercaptopurine (6-MP)
2. Azathioprine 3. Pentostatin |
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19. 6-Mercaptopurine (6-MP)
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6-MP is an inosine anologue that inhibits interonversions among purine nucleotides.
6-MP contains a sulfur atom in place of the keto group at C6 of the purine ring. After its entry into cells, MP is converted by HGPRT to the nucleotide form, 6-thioinosine-5'-monophosphate (T-IMP). |
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20. T-IMP is thought to inhibit purine nucleotide synthesis by several mechanisms - what are these mechanisms?
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1. T-IMP inhibits the enzymes that convert IMP to AMP and GMP, including inosine monophosphate dehydrogenase (IMPDH).
2. T-IMP (as well as AMP and GMP) is a feedback inhibitor of the enzyme that synthesizes phosphoribosylamine, which is the first step in purine nucleotide synthesisi. Both of these mechanisms lead to marked decreases in the cellular levels of AMP and GMP, which are essential metabolites for DNA synthesis, RNA synthesis, energy storage, cell signaling, and other functions. |
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21. Therapeutic uses of 6-MP
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The major clinical appilication of 6-MP is in acute lymphoblastic leukemia, especially in the maintenance phase of a prolonged combination chemo regimen.
Also useful for treatment in Crohn's disease. |
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22. Serious adverse effects of 6-MP
Contraindications? |
1. Pancreatitis
2. Myelosuppression 3. Hepatotoxicity 4. Infection 5. Gastritis Contraindicated in pregnancy |
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23. Azathioprine
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Azathioprine is a less toxic prodrug of 6-MP.
This prodrug is nonenzymatically converted to 6-MP in tissues. It is used for immunosuppression of autoimmune diseases. Adverse effects and contraindications are the same as for 6-MP |
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24. Therapeutic uses of azathioprine
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It is used for immunosuppression in renal transplantation, rheumatoid arthritis, and inflammatory bowel disease
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25. Allopurinol and 6-MP
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6-MP effectiveness and toxicity is increased by allopurinol.
Allopurinol inhibits xanthine oxidase, thereby preventing the oxidation of 6-MP to its inactive metabolite 6-thiouric acid. Coadministration of allopurinol with 6-MP allows the dose of 6-MP to be reduced by two-thirds. |
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26. Pentostatin
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Pentostatin is a selective inhibitor of adenosine deaminase (ADA). The drug is a structural analogue of the intermediate in the reaction catalyzed by ADA and binds to the enzyme with high affinity.
The resulting inhibition of ADA causes an increase in intracellular adenosine and 2'-deoxyadenosine levels. The increased adenosine and 2'deoxyadenosine have multiple effects on purine nucleotide metabolism. In particular, 2'-deoxyadenosine irreversibly inhibits S-adenosylhomocysteine hydrolase, and the resulting increase in intracellular S-adenosylhomocysteine is toxic to lymphocytes. |
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27. Therapeutic uses of pentostatin
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Especially effective against hairy cell leukemia.
Also used against T-cell lymphoma |
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28. Serious adverse effects of pentostatin
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1. Cardiac arrhythmia
2. Heart failure 3. Myelosuppression 4. Hepatotoxicity 5. Pulmonary toxicity |
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29. Common adverse effects of pentostatin
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1. Rash
2. Shaking chills 3. Vomiting 4. Myalgia 5. URI 6. Fever |
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30. Inhibitors of ribonucleotide reductase
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Hydroxyurea inhibits ribonucleotide reductase by scavenging a tyrosyl radical at the active site of the enzyme.
In the absence of this free radical, ribonucleotide reductase is unable to convert nucleotides to deoxynucleotides, and DNA synthesis is thereby inhibited. |
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31. Therapeutic uses for hydroxyurea
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Hydroxyurea is approved for use in the treatment of adult sickle cells disease and certain neoplastic diseases (i.e. head and neck cancer, melanoma, ovarian CA, hematologic malignancies)
Also used as a radiosensitizing agent. |
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32. Adverse effects of hydroxyurea
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1. Myelosuppresion
2. Secondary leukemia with long term use ---------------------------- 3. GI toxicity 4. Skin ulceration |
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33. Contraindications of hydroxyurea
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Severe bone marrow depression
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34. Therapeutic considerations for hydroxyurea
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Reduces tyrosine free radical critical to mechanism of action of ribonucleotide reductase.
In sickle cell anemia, hydroxyurea is thought o act by increasing HbF. |
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35. Purine and pyrimidine analogues that are incorporated into DNA
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These drugs are substrates for the vaious pathways of nucleotide metabolism, including ribosylation, ribonucleotide reduction, and nucleoside and nucleotide phosphorylation.
The sugar tri-phosphate forms of these drugs can then by incorporated into DNA. Once incorporated into DNA, these compounds disrupt the structure of DNA, resulting in DNA chain termination, DNA strand breakage, and inhibition of cell growth. |
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36. What are the names of the purine and pyrimidine analogues that are incorporated into DNA?
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1. Thioguanine
2. Fludarabine phosphate 3. Cladribine 4. Cytarabine (araC) 5. Azacytidine 6. Gemcitabine |
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37. Thioguanine
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Thioguanine is a guanine analogue in which a sulfur atom replaces the oxygen atom at C-6 of the purine ring. Thioguanine is converted by HGPRT to its nucleotide form, 6-thioguanosine-5'-monophosphate (6-thioGMP).
Unlike T-IMP, 6-thioGMP is a good substrate for guanylyl kinase, the enzyme that catalyzes the conversion of GMP to GTP. By this mechanism, 6-thioGMP is converted to 6-thioGTP, which is incorporated into DNA, causing cell death. 6-thioGMP also irreversibly inhibits IMPDH and thereby depletes cellular pools of GMP. |
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38. Therapeutic uses for thioguanine
Adverse effects? |
Used in the treatment of acute myelocytic leukemia.
Major adverse effects include bone marrow suppression and GI injury. |
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39. Fludarabine phosphate
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Fludarabine phosphate is a fluorinated purine nucleotide analogue that is structurally related to the antiviral agent vidarabine.
The triphosphate form of fludarabine is incorporated into DNA and RNA, cuasing DNA chain termination. Fludarabine triphosphate also inhibits DNA polymerise and ribonucleotide reductase and thereby decreases nucleotide and nucleic acid synthesis in cells. Used mainly in the treatment of lymphoproliferative disorders, esp chronic lymphocytic leukemia and low grade B-cell lymphomas and non-Hodgkin's lymphoma. |
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40. Adverse effects of fludarabine phosphate
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1. Aphasia of the skin
2. Autoimmune hemolytic anemia 3. Myelosuppression 4. Neurotoxicity 5. Pneumonia 6. Infection ------------------ 7. Edema 8. GI disturbance 9. Asthenia 10. Fatigue |
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41. Cladribine
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Cladribine is a chlorinated purine analogue that is structurally related to fludarabine phosphate.
Cladribine triphosphate is incorporated into DNA, causing strand breaks. Cladribine also depletes intracellular pools of the essential purine metabolites NAD and ATP. Cladribine is approved for use in the treatment of hairy cell leukemia and multiple sclerosis. |
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42. Adverse effect of cladribine
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1. Febrile neutropenia
2. Myelosuppresion 3. Neurotoxicity 4. Infection -------------- 5. Rash 6. Injection site reaction 7. Nausea 8. Headache |
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43. Cytarabine (araC)
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Cytarabine (araC) is a cytidine analogue that is metabolized to araCTP.
araCTP competes with CTP for DNA polymerase, and incorporation of araCTP into DNA results in chain termination and cell death. Cytarabine is used to induce and maintain remission in acute myelocytic leukemia; it is especially effective for this indication when combined with an anthracycline. |
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44. Therapeutic uses of Cytarabine (araC)
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1. Acute lymphoid leukemia
2. Acute myeloid leukemia 3. Chronic myeloid leukemia 4. Meningeal leukemia 5. Hodgkin's disease 6. Non-Hodgkin's lymphoma |
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45. Adverse effects of Cytarabine (araC)
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1. Myelosuppression
2. Neuropathy 3. Nephrotoxicity 4. Liver dysfunction 5. Infection --------------------- 6. Thrombophlebitis 7. Rash 8. Hyperuricemia 9. GI disturbance 10. Ulcers of the mouth or anus |
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46. Azacytidine
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5-Azacytidine is a cytidine analogue whose triphosphate metabolite is incorporated into DNA and RNA.
Once incorporated into DNA, azacytidine interferes with cytosine methylation, altering gene expression and promoting cell differentiation. Azacytidine is currently used in the treatment of myelodysplasia and is under investigation for use in the treatment of acute leukemias. |
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47. Adverse effects and contraindications of azacytidine
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1. Myelosuppresion
2. Renal failure ------------------------- 3. Peripheral edema 4. GI disturbance 5. Hepatic coma 6. Lethargy 7. Cough 8. Fever *Should not be used in patients with advanced malignant hepatic tumors. |
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48. Gemcitabine
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Gemcitabine is a fluorinated cytidine analogue in which the hydrogen atoms on the 2' carbon of deoxycytidine are replaced by fluorine atoms.
The diphosphate form of gemcitabine inhibits ribonucleotide reductase; the triphosphate form of gemcitabine is incorporated into DNA, interfering with DNA replication and resulting in cell death. |
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49. Therapeutic uses for gemcitabine
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1. Pancreatic CA
2. Nonsmall cell lung CA 3. Breast CA 4. Ovarian CA 5. Bladder CA 6. Sarcoma 7. Hodgkin's disease |
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50. Adverse effects and contraindications of gemcitabine
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1. Myelosuppression
2. Febrile neutropenia 3. Pulmonary toxicity 4. Hepatotoxicity 5. Hemolytic uremic syndrome ---------------- 6. Fever 7. GI disturbance 8. Liver enzyme elevations 9. Edema 10. Rash 11. Paresthesias *Should not be given during pregnancy. |
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51. Agents that directly modify DNA structure: alkylating agents
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Alkylating agents are electrophilic molecules that are attacked by nucleophilic sites on DNA, resulting in the covalent attachment of an alkyl group to the nucleophilic site.
Alkylating agents typically have two strong leaving groups, and this confers the ability to bis-alkylate, enabling the agent to crosslink the DNA molecule either to itself or to proteins. Bis-alkylation (crosslinking) seems to be the major mechanisms of cytotoxicity. |
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52. What are the agents that directly modify DNA structure: alkylating agents?
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1. Cyclophosphamide
2. Mechlorethamine 3. Melphalan 4. Estramustine 5. Chlorambucil 6. Mitomycin 7. Thiotepa 8. Carmustine 9. Dacarbazine 10. Procarbazine 11. Altretamine |
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53. Cyclophosphamide
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Alkylating agent that is particularly useful b/c it is a non-reactive prodrug that requires activation by the hepatic cytochrome P450; this agent can be administered either orally or via IV.
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54. Therapeutic uses of cyclophosphamide
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1. Autoimmune diseases
2. Leukemias and lymphomas 3. Advanced mycosis fungoides 4. Neuroblastoma 5. Ovarian cancer 6. Retinoblastoma 7. Breast CA 8. Malignant histiocytosis |
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55. Adverse effects and contraindications of cyclophosphamide
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1. Myelosuppression
2. Cardiomyopathy 3. Stevens-Johnson syndrome 4. Hemorrhagic cystitis 5. Azoospermia 6. Interstitial pneumonia 7. Infection ----------------------- 8. Alopecia 9. GI distrubance 10. Leukopenia 11. Amenorrhea *Do not give to patients w/severely depressed bone marrow function. |
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56. Mechlorethamine
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Alkylating agent that is used to treat leukemia and Hodgkin's disease.
Do not give to patients in the presence of a known infectious disease. |
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57. Melphalan
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Alkylating agent used to treat lymphoma
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58. Estramustine
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Alkylating agent used to treat prostate CA.
Do not give to patients with active thrombophlebitis or thromboembolic disorder. |
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59. Chlorambucil
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Alkylating agent used to treat leukemia.
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60. Mitomycin
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Alkylating agent used to treat gastric and pancreatic CA
Do not give to patients with a coagulation disorder or renal impairment. |
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61. Thiotepa
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Alkylating agent used to treat bladder CA.
Do not give to patients with hepatic, renal or bone marrow dysfunction. This medication is instilled directly in the bladder. |
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62. Carmustine
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Alkylating agent used to treat brain cancer.
Carmustine is a nitrosurea that attaches a carbamoyl group to target proteins. Requires bioactivation. |
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63. Dacarbazine
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Alkylating agent used to treat Hodgkin's disease and has some activity in treating melanoma and sarcomas.
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64. Procarbazine
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Alkylating agent used to treat Hodgkin's disease.
Do not give to patients with severe bone marrow depression. |
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65. Altretamine
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Alkylating agent used to treat Hodgkin's disease and refractory ovarian cancer.
Do not give to patients with severe bone marrow depression or severe neurologic toxicity. |
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66. Glutathione
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Highly reactive drugs can be deactivated by intracellular nucleophiles such as glutathione.
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67. O⁶-alkylguanine-DNA alkyltransferase
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This enzyme prevents permanent DNA damage by removing alkyl adducts to the O⁶ position of guanine before DNA crosslinks are formed.
Increased expression of this enzyme in neoplastic cells is associated with resistance to alkylating agents. |
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68. Acrolein and ifosfamide
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Acrolein is a byproduct of the activation of cyclophosphamide or its analogue ifosfamide. These can be produce hemorrhagic cystitis b/c of accumulation and concentration in the bladder.
This toxicity can be treated by using the sulfhydryl-containing molecule mesna, which is also concentrated in the urine and rapidly inactivates the acrolein. |
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69. Agents that directly modify DNA structure: platinum compounds
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These agents crosslink intrastrand guanine bases.
Includes: 1. Cisplatin 2. Carboplatin 3. Oxaliplatin |
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70. Cisplatin
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Consists of a platinum atom bound to two amines and two chlorines in the cis conformation.
As an antitumor agent, cisplatin is thought to act similarly to bis-alkylating agents by targeting nucleophilic centers in guanine, adenine and cytosine. The cis conformation allows the drug to form intrastrand crosslinks between adjacent guanine residues, resulting in DNA damage. |
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71. Therapeutic uses of cisplatin
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Genitourinary cancers, including cancers of the testis, bladder, and ovary.
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72. Adverse effects and contraindications of cisplatin
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1. Nephrotoxicity
2. Myelosuppresion 3. Peripheral neuropathy 4. Ototoxicity ------------------ 5. Electrolyte imbalance *Do not use in patients with severe bone marrow depression, or renal or hearing impairment. |
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73. Therapeutic considerations of cisplatin
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Cisplatin can be injected intraperitoneally for treatment of ovarian cancer.
Coadministration of amifostine with cisplatin can limit nephrotoxicity. |
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74. Carboplatin
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A cisplatin analogue associated with less nephrotoxicity - used to treat lung cancers
Same side effects and contraindications as cisplatin. |
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75. Oxaliplatin
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A third platinum compound, has activity in the treatment of colorectal CA.
Like cisplatin, oxaliplatin causes cumulative neurotoxicity; oxaliplatin also induces a unique acute neurotoxicity that is exacerbated by exposure to cold temperatures. |
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76. Adverse effects of oxaliplatin
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1. Acute and persistent neurotoxicity
2. Myelosuppression 3. Colitis 4. Hepatic dysfunction -------------------- 5. GI disturbance 6. Back pain 7. Cough 8. Fever |
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77. Bleomycin
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The bleomycins, a family of natural glycopeptides synthesized by a species of Streptomyces, have prominent cytotoxic activity.
Bleomycin binds DNA and chelates Iron (II), leading to the formation of free radicals that cause single and double strand DNA breaks. In chelating iron, bleomycin forms a heme-like ring which generates oxidative intermediates. |
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78. Therapeutic uses of bleomycin
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1. Testicular cancer
2. Hodgkin's disease 3. Non-Hodgkin's lymphoma 4. Squamous cell carcinoma |
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79. Adverse effects of bleomycin
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1. Pulmonary fibrosis*
2. Vascular disease 3. MI 4. Stroke 5. Raynaud's 6. Hepatotoxicity 7. Nephrotoxicity 8. Rare myelosuppression -------------------------- 9. Alopecia 10. Rash 11. Hyperpigmentation 12. Skin tenderness 13. GI disturbance 14. Stomatitis Most problematic and dose-limiting side effect. |
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80. Topoisomerase inhibitors
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These agents damage DNA by exploiting the natural nuclease/ligase function of topoisomerases.
They inhibit topoisomerase I or topoisomerase II, leading to DNA strand breakage. These include: 1. Camptothecins 2. Anthracycline 3. Epipodophyllotoxins 4. Amsacrine |
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81. Camptothecins
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Camptothecins target topoisomerase I. Topoisomerase I modulates supercoiling by complexing with DNA and nicking one of its two strands.
Camptothecins act by stabilizing this nicked DNA complex and preventing topoisomerase I from religating the strand break. These include: 1. Irinotecan 2. Topotecan |
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82. Irinotecan and topotecan
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Irinotecan is used to treat colorectal CA, but its use is limited by severe GI toxicity.
Topotecan is used to treat small cell lung CA, cervical CA, ovarian CA. This agent is especially useful in treating ovarian neoplasms that are resistant to cisplatin. Their action is specific to the S phase. |
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83. Adverse effect and contraindications of irinotecan and topotecan
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1. Life-threatening diarrhea
2. Myelosuppression 3. Febrile neutropenia 4. Liver dysfunction 5. Interstitial lung disease -------------------- 6. Alopecia 7. Eosinophilia |
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84. Anthracyclines
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Anthracyclines are natural antitumor antibiotics isolated from a species of the fungus Streptomyces, and are among the most clinically useful cytotoxic cancer chemotherapeutic agents.
They act on topoisomerase II, resulting in DNA lesions such as strand scission and, ultimately, in cell death. |
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85. What are the anthracyclines?
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1. Doxorubicin
2. Daunorubicin 3. Epirubicin 4. Etoposide 5. Amsacrine |
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86. Therapeutic uses of doxorubicin
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1. Leukemias
2. Lymphomas 3. Breast CA 4. Thyroid CA 5. Bladder CA 6. GI CA 7. Nephroblastoma 8. Osteosarcoma 9. Ovarian CA 10. Small cell CA of lung 11. Soft tissue sarcoma |
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87. Adverse effects and contraindications of doxorubicin
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1. Heart failure
2. Myelosuppression -------------------- 3. Alopecia 4. Rash 5. GI disturbance *Do not give to patients with severe bone marrow depression. |
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88. Therapeutic uses of daunorubicin
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Acute lymphoid leukemia and acute myeloid leukemia
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89. Therapeutic uses of epirubicin
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Breast CA
* Do not give to patients with severe hepatic dysfunction |
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90. Therapeutic uses of etoposide
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1. Testicular CA
2. Lung CA |
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91. Therapeutic uses of Teniposide
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1. Acute lymphoid leukemia
2. Non-Hodgkin's lymphoma |
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92. Therapeutic uses of Amsacrine
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1. Recurrent leukemia
2. Ovarian CA Inhibits topoisomerase II-mediated regulation of double-strand DNA breaks. This compound targets DNA by intercalating between base pairs, distorting the double helix, producing DNA-protein crosslinks, and creating both single and double strand DNA lesions. |
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93. Adverse effects of amsacrine
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1. ECG changes including QT prolongation
2. Paralytic ileus 3. Myelosuppression 4. Convulsion 5. Azoospermia 6. Hepatotoxicity ------------------------- 7. Alopecia 8. GI disturbance |
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94. Dexrazoxane
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Cardiotoxicity of doxorubicin can be reduced by coadministration of dexrazoxane, which is though to inhibit free radical formation by chelating intracellular iron and preventing iron-mediated free radical generation.
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95. Agents that inhibit microtubule polymerization
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These agents bind tubulin subunits and prevent microtubule polymerization.
Drugs that inhibit microtubule function are preferentially toxic to M-phase cells. Includes: vinblastine and vincristine |
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96. Therapeutic uses of vinblastine
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1. Metastatic testicular CA
2. Lymphoma 3. AIDS related Kaposi's sarcoma 4. Breast CA 5. Choriocarcinoma 6. Malignant histiocytosis 7. Mycosis fungiodes |
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97. Adverse effects of vinblastine and contraindications
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1. Myelosuppression
2. Hypertension 3. Neurotoxicity 4. Azoospermia --------------------- 5. Alopecia 6. Bone pain 7. GI disturbance *Do not give to patients with bacterial infection or significant ganulocytopenia. (Bone marrow suppression is dose limiting) |
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98. Therapeutic uses of vincristine
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1. Leukemias
2. Hodgkin's disease 3. Non-Hodgkin's lymphoma 4. Rhabdomyosarcoma 5. Nephroblastoma |
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99. Adverse effects of vincristine and contraindications
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1. Peripheral neuropathy
2. Myopathy 3. Myelosuppression ------------------------- 4. Alopecia 5. GI disturbance 6. Diplopia *Do not give to patients with Charcot-Marie-Tooth syndrome or for intrathecal use. (Peripheral neuropathy is dose limiting) |
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100. Vinca alkaloids vinblastine and vincristine
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Vinca alkaloids bind to β-tubulin on a portion of the molecule that overlaps with the GTP binding domain.
This leads to the depolymerization of existing microtubules. |
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101. What are the inhibitors of microtubule depolymerization?
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The taxanes, which include paclitaxel and docetaxel, are natural products originally derived from the bark of the western yew tree.
Taxanes bind to the β-tubulin subunit of microtubules at a site distinct from the vinca alkaloid binding site. Unlike the vinca alkaloids, taxanes promote microtubule polymerization and inhibit depolymerization. Stabilization of the microtubules in a polymerized state arrests cells in mitosis and eventually leads to the activation of apoptosis. |
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102. Paclitaxel
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Paclitaxel is used as an antineoplastic agent in the treatment of many solid tumors, especially breast, ovarian, and nonsmall cell lung CA.
Also used to treat AIDS related Kaposi's sarcoma. |
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103. Adverse effects and contraindications of paclitaxel
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1. Myelosuppression
2. Pulmonary toxicity 3. Severe hypersensitivity reaction (can be suppressed with dexamethasone and a histamine receptor antagonist) 4. Myopathy 5. Peripheral neuropathy (manifests as a "stocking and glove" sensory deficit) ----------------------------- 6. Alopecia 7. GI disturbance 8. Arthralgia *Do not give to patients with severe neutropenia. *Peripheral neuropathy is dose-limiting. |
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104. Abraxane
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AKA albumin-bound form of paclitaxel with a mean particle size of 130 nm. The albumin bound nanoparticles do not cause a hypersensitivity reaction, do not require premedication, and cause less myelosuppression than traditional, solvent-based paclitaxel.
This formation of paclitaxel may have greater antineoplastic activity than solvent-based paclitaxel. |
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105. Docetaxel
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Doxetaxel is used in treating:
1. Breast CA 2. Gastric CA 3. Prostate CA 4. Nonsmall cell lung CA Docetaxel does not cause neuropathy as frequently as paclitaxel; the myelosuppression associated with docetaxel is profound, however, and is usually dose-limiting. |
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106. Adverse effects and contraindications of Doxetaxel
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1. Myelosuppression
2. Stevens-Johnson syndrome 3. Fluid retention syndrome leading to severe edema 4. Neuropathy 5. Hepatotoxicity 6. Colitis ---------------------------- 7. Alopecia 8. GI disturbance 9. Asthenia 10. Fever *Do not give to patients with severe neutropenia. *Myelosuppression is dose-limiting. |
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107. Telomerase inhibitors
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AThe observation that telomerase is expressed in most CA cells and is a key component of the process of immortalization highlights this enzyme as an important target in future cancer therapy.
Although telomerase is expressed to some degree in stem cells and in normally cycling cells, most normal cells lack telomerase expression. Therefore, the dependency of tumor cells on the immortalized state could provide telomerase inhibitors with a favorable therapeutic index. |
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108. PARP1 inhibitors
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PARP1 inhibitors are thought to represent promising new agents in the treatment of BRCA1- or BRCA2-deficient breast or ovarian CA, and may be effective in other tumors in which the DNA damage response is compromised.
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109. What are the three important features of brain tumors?
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1. Consequences of location
-the ability to remove the neoplasm surgically may be restricted by functional anatomic considerations. Benign lesions can have lethal consequences b/c of their location. 2. Patterns of growth -most glial tumors, including many w/histologic features of a benign neoplasm, infiltrate entire regions of the brain leading to clinically malignant behavior. 3. Patterns of spread -some types of tumor spread through the CSF; however, even the most frankly malignant gliomas rarely metastasize outside the CNS. |
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110. Tumors of the CNS in children vs. adults
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Tumors of the CNS account for as many as 20% of all cancers of childhood.
In this age group, 70% of primary tumors arise in the posterior fossa, whereas in adults, a corresponding proportion arise above the tentorium. Among adults, there is a nearly equal incidence of primary and metastatic tumors. |
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111. Fibrillary (diffuse) astrocytomas
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Fibrillary (diffuse) astrocytomas represent about 80% of adult primary brain tumors, usually in the cerebral hemispheres, but they may also occur in the cerebellum, brain stem, or spinal cord.
All astrocytomas are composed of neoplastic astrocytic nuclei, distributed amid astrocytic processes of varying density; grade is determined histologically. |
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112. Features of fibrillary (diffuse) astrocytomas
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Well-differentiated tumors (astrocytomas) are poorly defined, gray-white, infiltrative tumors that expand and distort a region of the brain; they show hypercellularity and some nuclear pleomorphism.
These are WHO grade II/IV tumors. |
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113. hat are the four major classes of brain tumors?
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1. Gliomas
-derived from glial cells, include astrocytomas, oligodendrogliomas, and ependymomas. 2. Neuronal tumors -includes gangliocytomas, gangliogliomas and papillary glioneuronal tumors. 3. Poorly differentiated neoplasms -includes medulloblastomas and atypical teratoid/rhabdoid tumors 4. Meningiomas -includes atypical meningiomas and anaplastic meningiomas |
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114. Anaplastic astrocytomas
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More anaplastic and aggressive tumors (anaplastic astrocytomas) reveal increased nuclear anaplasia and the presence of mitoses and vascular cell proliferation.
These are WHO grade III/IV tumors. |
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115. Glioblastomas
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Extremely high-grade tumors (gliobastomas) are composed of a mixture of firm, white areas; softer yello foci of necrosis; cystic change; and hemorrhage.
Increaded nuclear density of the highly anaplastic tumor cells along the edges of the necrotic regions is termed pseudopalisading. These are WHO grade IV/IV tumors. |
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116. Low grade astrocytomas
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May remain static or progress only slowly for a number of years. Eventually, however, patients often enter a period of rapid clinical deterioration and rapid tumor growth, corresponding to the appearance of anaplastic features.
The prognosis for patients with glioblastoma is poor: mean length of survival after diagnosis is only 8-10 months. |
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117. Pilocytic astrocytomas
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Occur in children and young adults, usually in the cerebellum but also in the floor of the walls of the third ventricle, the optic nerves, and occasionally, the cerebral hemispherses.
They are often cystic with a mural nodule in the wall of the cyst. The tumor is composed of bipolar cells w/long, thin hairlike processes. Rosenthal fibers and microcysts are often present. These tumors are rarely infiltrative and grow slowly. They are WHO grade I/IV tumors. |
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118. Pleomorphic xanthoastrocytomas
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Occur most often relatively superficially in the temporal lobes of children and young adults w/a history of seizures.
They contain neoplastic astrocytes, sometimes with bizarre forms, abundant reticulin and lipid deposits, and chronic inflammatory cell infiltrates. |
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119. Brain stem gliomas
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Occur mostly in the first 2 decades of life. By the time of autopsy, about 50% have progressed to glioblastomas.
With radiotherapy, the 5-year survival rate is 20-40%. |
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120. Molecular genetics of glioblastic tumors
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Secondary glioblastomas shared p53 mutations that characterized low grade gliomas, while primary glioblastomas were characterized by amplification of the epidermal growth factor receptor gene.
In addition to these two changes, there are certain other genetic alterations that mark the two pathways to gliobastoma: PDFG-A amplification in secondary gliobastomas, and MDM2 overexpression, p16 deletion, or PTEN mutations in primary glioblastomas. |
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121. Oligodendrogliomas
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Constitute about 5-15% of gliomas and are most common in middle life in the cerebral white matter.
In general, patients with oligodendrogliomas have a better prognosis than patients with astrocytomas. Current therapies yield an average survival time of 5-10 years. Cases of poorly differentiated tumors w/increased anaplasia, mitotic activity, cell density, and necrosis have a worse prognosis. |
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122. Morphology of oligodendrogliomas
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Oligodendrogliomas are well-circumscribed, gelatinous, gray masses, often w/cysts, focal hemorrhage, and calcification.
The tumor consists of sheets of regular cells w/round nuclei containing finely granular chromatin, often surrounded by a clear halo of cytoplasm sitting in a delicate network of anastomosing capillaries. Calcification, present in up to 90% of cases, ranges from microscopic foci to massive deposits. |
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123. Ependymomas
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These tumors arise from the ependymal lining of the ventricular system, including the central canal of the spinal cord.
CSF dissemination is a common finding. The NF2 gene on chromosome 22 has been examined as a candidate locus for alterations in ependymomas. It appears that alterations at this site may be involved in the pathogenesis of edendymomas in the spinal cord but not at other sites. |
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124. Age of onset of ependymomas and location
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In the first 2 decades of life, ependymomas typically occur in the fourth ventricle; in middle life, the spinal cord is the most common location.
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125. Morphological characteristics of ependymomas
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The tumor cells have regular, round-oval nuclei w/abundant granular chromatin.
They may form ependymal rosettes (canals) or, more frequently, perivascular pseudorosettes. |
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126. Myxopapillary ependymomas
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These are histologically benign lesions arising in the filum terminale of the spinal cord.
Cuboidal cells, sometimes w/clear cytoplasm, are arranged around papillary cores containing connective tissue and blood vessels. Myxoid areas contain neutral and acidic mucopolysaccharides. |
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127. Subependymomas
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These are solid, sometimes calcified, slow-growing nodules attached to the ventricular lining and protruding into the ventricle.
They have clumps of ependymomal-appearing nuclei scattered in a dense, finely fibrillar background. |
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128. Choroid plexus papillomas
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These almost exactly recapitulate the structure of the normal choroid plexus, with papilae of connective tissue stalks covered with a cuboidal or columnar ciliated epithelium.
Hydrocephalus is common, as a result of either obstruction of the ventricular system or overproduction of CSF. In children, the lateral ventricles are the most common site; in adults, the fourth ventricle is a more frequent site. |
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129. Colloid cysts of the third ventricle
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These are non-neoplastic lesions of young adults; they are located at the foramina of Monro and can result in noncommunicating hydrocephalus, sometimes rapidly fatal.
The cyst has a thin, fibrous capsule and a lining of low to flat cuboidal epithelium; the cyst contents are gelatinous proteinaceous material. |
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130. Ganglion cell tumors
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A type of neuronal tumor; a ganglioglioma is a neoplasm w/an admixed ganglion cell component of irregularly clustered neurons w/apparently random orientation of neurites and frequent binucleated forms.
Most occur in the temporal lobe and are slow growing, but occasionally the glial component becomes frankly anaplastic; the tumor then assumes a much more aggressive course. |
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131. Gangliocytoma
|
Mature-appearing neurons may constitute the entire population of a tumor, in which case it is termed a gangliocytoma.
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132. Dysembryoplastic neuroepithelial tumor
|
A tumor of childhood often presenting as a seizure disorder, with a relatively good prognosis after resection.
Features include intracortical location, cystic changes, nodular growth, "floating neurons" in a pool of mucopolysaccharide-rich fluid, and surrounding neoplastic glia w/o anaplastic features. |
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133. Cerebral neuroblastomas
|
This is a tumor with only neuronal elements.
This rare, aggressive neoplasm occurs in the hemispheres in children and resembles peripheral neuroblastomas, with small undifferentiated cells and Homer-Wright rosettes. |
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134. Neurocytomas
|
This is another tumor with only neuronal elements.
This tumor is found adjacent to the foramen of Monro. Evenly spaced, round, uniform nuclei resemble cells of an oligodendroglioma, but ultrastructural and immunohistochemical studies reveal their neuronal origin. |
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135. Poorly differentiated neoplasms
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Some tumors, although of neuroectodermal origin, express few, if any, of the phenotypic markers of mature cells of the nervous system and are described as poorly differentiated.
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136. Medulloblastomas
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Medulloblastomas account for 20% of childhood brain tumors; they occur exclusively in the cerebellum.
Tumors are located in the midline in children, with lateral locations found more often in adults. Rapid growth may occlude the flow of CSF, leading to hydrocephalus. The tumor is highly malignant, and the prognosis for untreated neoplasm is dismal; however, it is exquisitely radiosensitive. With total excision and radiation, the 5-yr survival rate is 75%. |
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137. Morphological characteristics of medulloblastomas
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They are often well circumscribed, gray, and friable. They are usually extremely cellular, with sheets of anaplastic cells exhibiting hyperchromatic nuclei and abundant mitoses.
The cells have little cytoplasm, and the cytoplasm is often devoid of specific markers of differentiation, although neuronal or glial features may be seen. Extension into the subarachnoid space may elicit a prominent desmoplastic response. Dissemination through the CSF is common. |
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138. Primary CNS lymphoma
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Primary brain lymphomas account for approx 2% of extranodal lymphomas.
One or more dominant masses occur within the brain parenchyma; nodal or bone marrow involvement and involvement outside the CNS are extremely rare late complications. |
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139. Immunosuppressed patients and primary brain lymphoma
|
Within the immunosuppressed population (e.g. AIDS), all the neoplasms appear to be of B-cell origin and to contain Epstein-Barr virus genomes within the transformed B cells.
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140. Clinical characteristics of primary brain lymphoma
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The primary brain lymphoma is an aggressive disease w/relatively poor chemotherapeutic responses compared with peripheral lymphoma.
Nevertheless, it is initially responsive to radiotherapy and steroids. |
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141. Morphological characteristics of primary brain lymphoma
|
The morphology of the neoplastic lymphocytes is nearly always of a high grade type.
The malignant cells diffusely involve the parenchyma of the brain and accumulate around blood vessels, with some vessel walls expanded by multiple layers of malignant cells. |
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142. Germ cell tumors
|
These tumors occur along the midline in adolescents and young adults, with the pineal and suprasellar regions dominating the distribution.
Tumors in the pineal region show a strong male predominance, not seen in suprasellar lesions. The histologic appearances of germ cell tumors and their classification are the same as used for other extragonadal sites. |
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143. Meningiomas
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Meningiomas are predominantly benign tumors of adults that arise from the meningothelial cell of the arachnoid.
They show a moderate (3:2) female predominance within the cranial vault but a 10:1 female-male ratio within the spinal canal. Loss of heterozygosity of the long arm of chromosome 22 is a common finding. |
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144. Morphological characteristics of meningiomas
|
Meningiomas tend to be rounded masses w/well-defined dural bases that compress the underlying brain but are easily separated from it.
Lesions are usually firm to fibrous and lack evidence of necrosis or extensive hemorrhage. Many histologic patterns exist, all with generally comparable favorable outcomes. |
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145. What are the histologic patterns of meningiomas?
|
1. Syncytial
2. Fibroblastic 3. Transitional 4. Psammomatous 5. Papillary tumors 6. Malignant meningiomas 7. Sarcomas of the meninges |
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146. Synctial meningiomas
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Clusters of cells in tight groups without visible cell membranes
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147. Fibroblastic meningiomas
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Elongated cells and abundant collagen deposition.
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148. Transitional meningiomas
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Feature of the syncytial and fibroblastic types.
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149. Psammomatous meningiomas
|
Abundant psammoma bodies, apparently forming from calcification of the syncytial nests of meningothelial cells.
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150. Papillary meningioma tumors
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Pleomorphic cells arranged around fibrovascular cores (tend to have worse prognosis)
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151. Anaplastic (malignant) meningiomas
|
Unusual tumors that may be difficult to recognize histologically as being meningothelial.
They have abundant mitoses w/atypical forms. |
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152. Sarcomas of the meninges
|
Uncommon but can include malignant fibrous histiocytomas and hemangiopericytomas.
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153. Atypical meningiomas
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These are lesions with a higher rate of recurrence and more aggressive local growth that may require therapy in addition to surgery.
The Dx criteria for this requires either a mitotic index of 4 or more mitoses per 10 high power fields or 3 or more of the atypical features: 1. Increased cellularity 2. Small cells w/a high nuclear:cytoplasmic ratio 3. Prominent nucleoli 4. Patternless growth 5. Necrosis |
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154. Molecular genetics of meningiomas
|
The most common cytogenetic abnormality is loss of chromosome 22, especially the long arm (22q).
The deletions include the region of 22q12 that harbors the NF2 gene. Indeed, 50-60% of meningiomas not associated w/neurofibromatosis type 2 have mutations in the NSF2 gene; the majority of these mutations are predicted to result in absence of functional protein. |
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155. Meningiomas and neurofibromatosis type 2
|
Lesions are usually solitary, and their presence at multiple sites, especially in association with acoustic neuromas or glial tumors, suggests a Dx of neurofibromatosis type 2.
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156. Metastatic tumors
|
Among general hospital patients, metastatic lesions, mostly carcinomas, account for approx half of intracranial tumors.
Common primary sites are lung, breast, skin (melanoma), kidney, and GI tract. The meninges are also a frequent site for involvement by metastatic disease. |
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157. Morphology of intraparenchymal metastatic tumors
|
Intraparenchymal metastases are sharply demarcated masses, often at the gray-white junction, usually surrounded by a zone of edema.
Meningeal carcinomatosis, with tumor nodules studding the surface of the brain, spinal cord, and intradural nerve roots, is an occasional complication particularly associated w/small cell carcinoma, adenocarcinoma of the lung, and carcinoma of the breast. |
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158. Paraneoplastic syndromes
|
Paraneoplastic syndromes are functional and structural changes of the brain in response to malignancy elsewhere in the body.
The major underlying mechanism involves the systemic development of an immune response against tumor antigens that can cross-react w/antigens in the CNS or PNS. Syndromes may improve with plasmapheresis, immunosuppression, or treatment of the primary neoplasm. |
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159. Paraneoplastic cerebellar degeneration
|
This is the most common pattern, with loss of Purkinje cells, gliosis, and mild inflammatory infiltrate associated w/an antibody-mediated injury of Purkinje cells.
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160. Limbic encephalitis
|
This is a subacute dementia, usually with a prominent component of memory disturbance.
Findings are most striking in the anterior and medial portions of the temporal lobe and resemble an infectious process w/perivascular inflammatory cuffs, microglial nodules, some neuronal loss, and gliosis. A comparable process involving the brainstem an be seen in isolation or together with limbic system involvement. |
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161. Subacute sensory neuropathy
|
Occurs in association with limbic encephalitis or in isolation, with loss of sensory neurons from dorsal root ganglia, in association with inflammation.
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162. Eye movement disorders in paraneoplastic syndromes
|
Eye movement disorders, most commonly opsoclonus, may be found, often in association with other evidence of cerebellar and brainstem dysfunction.
In children, this is most commonly associated w/neuroblastoma and is found along with myoclonus. |
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163. Peripheral nerve sheath tumors
|
A large proportion of tumors occurring within the confines of the dura are derived from cells of peripheral nerve (including Schwann cells, perineurial cells, and fibroblasts).
Comparable tumors arise along the peripheral course of nerves. |
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164. Schwannomas
|
Schwannomas are benign tumors of neural crest-derived Schwann cells, most commonly associated w/the vestibular branch of CN VIII at the cerebellopontine angle (vestibular schwannoma or acoutic neuroma).
Spinal tumors mostly arise from dorsal roots; tumors may extend through the vertebral foramen, acquiring a dumbbell configuration. When extradural, schwannomas are most commonly found in association with large nerve trunks. |
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165. Morphological characteristics of schwannomas
|
They are well-circumscribed, encapsulated masses, attached to the nerve but separable from it. Axons are excluded from the tumors, although they may becomes entrapped in the capsule.
Electron microscopy shows basement membrane deposition encasing single cells and long-spacing collagen. Malignant change is extremely rare. Tumors show a mixture of two growth patterns: Antoni A and Antoni B |
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166. Antoni A growth pattern in schwannomas
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Elongated cells with cytoplasmic processes arranged in fascicles in areas of moderate-to-high cellularity with little stromal matrix.
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167. Antoni B growth pattern in schwannomas
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Less densely cellular tissue with microcysts and myxoid changes.
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168. Neurofibromas
|
Two histologically, and perhaps biologically, distinct lesions have been termed neurofibromas.
The most common form occurs in the skin (cutaneous neurofibroma) or in peripheral nerve (solitary fibroma). They arise sporadically or in association with neurofibromatosis Type 1. The second type is plexiform neurofibroma, which is considered by some to occur only in patients with NF1. |
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169. Cutaneous neurofibroma and solitary neurofibroma
|
They occur sporadically an in association w/NF1.
The skin lesions are evident as nodules, sometimes with hyperpigmentation; these lesions may grow quite large and become pedunculated. Present in the dermis and extending to the subcutaneous fat, these are well-delineated but unencapsulated masses composed of spindle cells in highly collagenized stroma. Lesions within peripheral nerves are histologically similar. |
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170. Plexiform neurofibromas
|
They irregularly expand a nerve as fascicles are infiltrated. In contrast to schwannomas, it is not possible to separate the lesion from the nerve, making surgical removal difficult.
The lesion has a loose myxoid background w/a low cellularity, including Schwann cells, fibroblasts, perineurial cells, and a sprinkling of inflammatory cells, often including mast cells. Axons can be found within the tumor. |
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171. Malignant peripheral nerve sheath tumor (AKA malignant Schwannoma)
|
These highly malignant, locally invasive sarcomas do not arise from malignant degeneration of schwannomas; instead, they arise de novo or from transformation of a plexiform neurofibroma.
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172. Morphological characteristics of malignant Schwannomas
|
The lesions are poorly defined tumor masses with frequent infiltration along the axis of the parent nerve as well as invasion of adjacent soft tissues.
Tumor cells represent Schwann cells w/elongated nuclei and prominent bipolar processes; fascicle formation may be present. Mitoses, necrosis, and nuclear anaplasia are common. |
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173. Epitheliod malignant schwannomas
|
These are aggressive variants derived from nerve sheaths and contain tumors cells having visible cell borders and epithelial type nests.
They are immunoreactive for S-100 but not for keratin, the latter differentiating them from epithelial tumors. |
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174. Familial tumor syndromes
|
These mostly autosomal dominant disorders are characterized by hamartomas and neoplasms located throughout the nervous system and skin.
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175. Neurofibromatosis type 1 (NF1)
|
This autosomal dominant disorder is characterized by neurofibromas (plexiform and cutaneous), optic nerve gliomas, meningiomas, pigmented nodules of the iris (Lisch nodules), and cutaneous hyperpigmented macules (cafe au lait spots).
Even in the absence of malignant transformation of neurofibromas, lesions have disfiguring potential and the potential to create spinal deformity (i.e. kyphoscoliosis). |
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176. The NF1 gene
|
The NF1 gene is a tumor suppressing gene, based on evidence of loss of heterozygosity in tumors from NF1 patients.
It is located at 17q11.2 has been identified and encodes a protein termed neurofibromin. The protein contain a region homologous to the RAS family of GTPase-activating proteins, and it is presumed that neurofibromin plays a roles in regulating signal transduction. The protein is widely expressed, the highest levels being found in neural tissue. |
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177. Molecular genetics of neurofibromatosis type 1 (NF1)
|
A variety of mutations involving the NF1 gene have been detected. The clinical phenotype does not correlate with the type or location of the NF1 mutation.
The course of the disease is highly variable; some individuals who carry a mutated gene have no symptoms, while other develop progressive disease with spinal deformities, disfiguring lesions, and compression of vital structures, including the spinal cord. |
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178. Neurofibromatosis type 2 (NF2)
|
This distinct autosomal dominant disorder (chromosome 22) has a propensity to develop bilateral eighth nerve schwannomas or multiple meningiomas.
Gliomas, typically ependymomas of the spinal cord, also occur in these patients. This disorder is much less common than NF1, having a frequency of 1/40,000 to 1/50,000. |
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179. Molecular genetics of neurofibromatosis type 2 (NF2)
|
The NF2 gene is located on chromosome 22q12, and the gene product, merlin, shows structural similarity to a series of cytoskeletal proteins.
Nonsense mutations usually cause a more severe phenotype than missense mutations. |
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180. Tuberous sclerosis
|
Characterized by angiofibromas, seizures, and mental retardation.
Hamartomas within the CNS include cortical tubers and subependymal hamartomas. In addition, renal angiomyolipomas; retinal glial phakomas; cardiac rhabdomyomas; hepatic, renal and pancreatic cysts; leathery cutaneous thickenings (shagreen patches); hypopigmented areas; and subungual fibromas may occur. |
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181. Cortical tubers
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Areas of haphazardly arranged neurons and large cells that express phenotypes intermediate between glia and neurons.
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182. Subependymal hamartomas
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Large astrocytic and neuronal cell clusters beneath the ventricular surface that give rise to a tumor unique to tuberous sclerosis - the subependymal giant cell astrocytoma.
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183. Molecular genetics of tuberous sclerosis
|
There is variable expressivity and penetrance, and at least two distinct loci are known, on chromosomes 9 (hamartin) and 16 (tuberin).
The complex containing these proteins may play a role in regulating cell proliferation. |
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184. von Hippel-Lindau disease
What are the four characteristics of this disease? |
Characterized by:
1. Capillary hemangioblastomas in the cerebellar hemispheres, retina, and less commonly w/in the brain stem and spinal cord. 2. Cysts involving the pancreas, liver, and kidney, with a strong propensity to develop renal cell carcinoma of the kidney. 3. Paragangliomas 4. Hemangioblastomas containing variable proportions of delicate capillary vessels with stromal cells of uncertain histogenesis and abundant vacuolated cytoplasm between them. |
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185. Morphology of von-Hippel-Lindau disease
|
The cerebellar capillary hemangioblastoma, the principal neurologic manifestation of the disease, is a highly vascular neoplasm that occurs as a mural nodule associated w/a large fluid-filled cyst.
On microscopic exam, the lesion consists of a mixture of variable proportions of capillary-size or somewhat larger thin walled vessels with intervening stromal cells of uncertain histogenesis, characterized by vacuolated, lightly PAS-positive, lipid rich cytoplasm and indefinite immunohistochemical phenotype. |
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186. Clinical features of von-Hippel-Lindau disease
|
They commonly are cystic lesions with a mural node.
Polycythemia is an associated finding in about 10% of cases, related to erythropoietin production by the tumor. Treatment is directed at the symptomatic neoplasms, including resection of the cerebellar hemangioblastomas and laser therapy for retinal hemangioblastomas. Partial nephrectomy is performed for renal carcinomas when these malignant neoplasms are bilateral. |
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187. Hydrocepahalus
|
Caused by excess CSF in the intracranial cavity.
This condition can result from: 1. Excess CSF production 2. Obstruction of flow at any point in the ventricles or subarachnoid space 3. Decrease in reabsorption via the arachnoid granulations. |
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188. Excess CSF production
|
Quite rare as a cause of hydrocephalus; it is seen only in certain tumors, such as choroid plexus papilloma.
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189. Obstruction of CSF flow
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Can be produced by obstruction of the ventricular system by tumors, intraparenchymal hemorrhage, other masses, and congenital malformations.
This can occur anywhere along the path of CSF flow, but especially at narrow points such as the foramen of Monro, the cerebral aqueduct, or the fourth ventricle. Can also occur outside the ventricles in the subarachnoid space as a result of debris or adhesions from prior hemorrhage, infection, or inflammation |
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190. Decreased CSF reabsorption
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Can cause hydrocephalus when the arachnoid granulations are damaged or clogged.
Decreased reabsorption at the arachnoid granulations is difficult to distinguish clinically from obstruction of CSF flow in the subarachnoid space, an often has similar causes. |
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191. What are the two categories of hydrocephalus?
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1. Communicating hydrocephalus
2. Noncommunicating hydrocephalus |
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192. Communicating hydrocephalus
|
Caused by impaired CSF reabsorption in the arachnoid granulations, obstruction of flow in the subarachnoid space, or by excess CSF production
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193. Noncommunicating hydrocephalus
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Caused by obstruction of flow within the ventricular system.
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194. Main symptoms and signs of hydrocephalus
|
Similar to those of any other cause of elevated intracranial pressure and can be acute or chronic.
1. Headache 2. Nausea 3. Vomiting 4. Cognitive impairment 5. Decreased level of consciousness 6. Papilledema 7. Decreased vision 8. Sixth-nerve palsies 9. Magnetic gait 10. Incontinence |
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195. Parinaud's syndrome
|
In more severe cases of hydrocephalus, dilation of the suprapineal recess of the posterior third ventricle can push downward onto the collicular plate of the midbrain.
The important abnormality to be aware of is limited vertical gaze, especially in the upward direction. |
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196. Normal pressure hydrocephalus
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A condition sometimes seen in elderly individuals that is characterized by chrnoically dilated ventricles.
Patients typically present w/the clinical triad of gait difficulties, urinary incontinence, and mental decline. CSF pressure is not usually elevated; problems may result from impaired CSF reabsorption at the arachnoid villi. |
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197. What are the most common brain tumors?
|
1. Glioblastoma
2. Brain metastases 3. Meningioma 4. Astrocytoma 5. Pituitary adenoma 6. Schwannoma 7. Ependymoma |
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198. Gliomas
|
Divided into several types:
Glial tumors arising form astrocytes are called astrocytomas Classified using the Daumas-Dupont grading system, in which the most malignant is grade IV/IV, or glioblastoma multiforme. Unfortunately, glioblastoma is relatively common and usually leads to death within 1 year despite maximal resection, radiation, and chemotherapy. |
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199. Meningiomas
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Arise from the arachnoid villus cells an occur, in order of decreasing frequency, over the lateral convexities, in the falx, and along the basal regions of the cranium.
They grow slowly and appear on CT and MRI scans as homogeneous enhancing areas that arise from the meningeal layers. In female patients, meningiomas are associated with breast cancer. Treated by local excision. |
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200. Pituitary adenomas
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Can cause endocrine disturbances or compress the optic chiasm, usually resulting in a bitermporal visual field defect.
Treatment with dopaminergic agonists often will shrink the tumors. |
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201. Lymphoma of the CNS
|
Has been on this rise in recent years in part due to the increase in HIV.
This neoplasm arises from B lymphocytes and commonly involves regions adjacent to ventricles. It can often be controlled for several years with chemotherapy and radiation therapy and currently has a median survival rate of close to four years. |
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202. Pineal region tumors
|
Relatively uncommon and include pinealomas, germinoma, and rarely teratoma or glioma.
Tumors in this region may obstruct the cerebral aqueduct, causing hydrocephalus, or may compress the dorsal midbrain, causing Parinaud's syndrome. |
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203. What is the most tumor-causing brain hemorrhage?
|
Lung cancer, simply b/c the incidence of lung cancer and metastases to the brain is so high.
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204. Paraneoplastic syndromes
|
Relatively rare neurologic disorders caused by remote effects of cancer in the body, thought to result from autoimmune mechanisms.
Examples include limbic or brainstem encephalitis, cerebellar Purkinje cell loss, spinal cord anterior horn cell loss, neuropathy, impaired neuromuscular transmission, and opsoclonus myoclonus, which is characterized by irregular jerking movements of the eyes and limbs. Tumors that most often cause paraneoplastic syndromes include small cell lung carcinoma, breast cancer, and ovarian cancer. |
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205. Infectious meningitis
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Infection of the CSF in the subarachnoid space. It can be caused by bacteria, viruses, fungi, or parasites.
Except for in elderly, very young, or immunocompromised patients, it is usually heralded by marked signs and symptoms of meningeal irritation, or meningismus. |
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206. Common features of meningeal irritation
|
1. Headache
2. Lethargy 3. Phototopia 4. Phonophobie 5. Fever 6. Nuchal rigidity |
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207. Bacterial meningitis
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CSF typically has a high WBC count with a PMN predominance, high protein, and low glucose.
Most common pathogens vary on the aptient's age. Treatment, therefore, also depnds on age. Complications include seizures, cranial neuropathies, cerebral edema, hydrocephalus, herniation, cerebral infarcts, and death |
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208. Brain abscess
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Another important bacterial infection of the nervous system.
Presents as an expanding intracranial mass lesion, much like a brain tumor, but often with a more rapid course. Common presenting features include headache, lethargy, fever, nuchal rigidity, nausea, vomiting, seizures, and focal signs determined by the location of the abscess. Fever is not always present, making the Dx of infection more difficult. The ESR is usually elevated. |
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209. What are the common infecting organisms in brain abscesses?
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1. Streptococci
2. Baceroides 3. Enterobactericeae 4. S. Aureus 5. Nocardia Treatment with antibiotics. *Toxoplasma gondii is also another cause of brain abscess other than bacteria. |
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210. Epidural abscess
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Can occasionally occur in the spinal canal, and requires prompt diagnosis and treatment.
Common presenting features include back pain, fever elevated peripheral WBC count, headache, and signs of nerve root or spinal cord compression. Complications include spinal cord compression, paraparesis, and urinary and fecal incontinence. Treated with surgical drainage and antibiotics. Common organisms are S. Aureus, streptococci, gram-negative bacilli, and anaerobes. |
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211. Subdural empyema
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A collection of pus in the subdural space, usually resulting from direct extension from an infection of the nasal sinuses or inner ear.
This condition is treated by urgent surgical drainage and antibiotics. |
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212. Tuberculous meningitis
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Presents with headache, lethargy, and meningeal signs usually appear over the course of several weeks.
There is often an inflammatory response in the basal cisterns of the brain, which can affect the circle of Willis vessels. If untreated, coma, hydrocephalus, and death ensue. |
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213. Meningeal involvement in tuberculous meningitis results from...?
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Reactivation of previous tuberculosis infection, and signs of pulmonary tuberculosis are often not present at the time of presentation.
CSF fluid shows an elevated WBC count w/lymphocyte predominance, elevated protein and low glucose. |
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214. What organism is responsible for tuberculous meningitis?
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Mycobacterium tuberculosis.
Dx can be confirmed by culture, which takes several weeks, or more recently, by PCR. Treated w/a combo of isoniazid, rifampin, ethambutol, and pyrazinamide. |
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215. Neurosyphilis
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Caused by the spirochete Treponema pallidum. Transmitted sexually and has various stages that occur at different times after primary infection.
Only in tertiary syphilis do neurologic symptoms present |
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216. Aseptic meningitis in neurosyphilis
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Meningeal involvement can cause aseptic meningitis, sometimes associated w/cranial nerve palsies, especially involving the optic, facial, and vestibulocochlear nerves.
Later stages can occur following a latency of about 4-15 years. - These are classified as meningovascular syphilis, general paresis, and tabes dorsalis. |
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217. Meningovascular syphilis
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Chronic meningeal involvement causes an arteritis, typically involving medium-sized vessels, that results in diffuse white matter infarcts.
If untreated, this leads to general paresis. |
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218. General paresis
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The accumulation of lesions causes dementia, behavioral changes, delusions of grandeur, psychosis, and diffuse upper motor neuron-type weakness.
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219. Tabes dorsalis
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Another variant that often coexists w/general paresis. Patients have involvement of the spinal cord dorsal roots, especially in the lumbosacral region, resulting in degeneration of the dorsal columns.
Therefore, these patients have sensory loss in the lower extremities, sensory ataxia with a characteristic high stepping tabetic gait, and incontinence. Other associated features include Argyll Robertson pupils and optic atrophy. |
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220. Dx of neurosyphilis
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Based on blood tests for treponemes, together with CSF showing lymphocyte-predominant meningitis.
Treated w/IV penicillin G, and serial lumbar punctures should be performed to monitor the response to therapy. |
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221. Lyme disease
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Caused by the spirochete Borrelia burgdorferi, carried by Ixodes species of deer tick, which are endemic to certain areas of the US, Europe, and Australia.
Primary infection is often heralded by a characteristic raised rash, which gradually shifts its location and enlarges over days to weeks. In some cases, neurologic manifestations occur; these usually appear after a delay of several weeks and include a lymphocyte predominant meningitis or mild meningoencephalitis, characterized by meningeal signs and emotional change, with impaired memory and concentration |
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222. Dx & treatment of Lyme disease
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Via typical clinical features, lumbar puncture, and serological testing.
Untreated cases can eventually show white matter abnormalities on MRI scan. Lyme disease w/neurologic involvement is treated w/IV ceftriaxone |
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223. Viral meningitis
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Tends to be less fulminant than bacterial meningitis, and recovery usually occurs spontaneously within 1-2 weeks.
Patient presents w/headache, fever, lethargy, nuchal rigidity, and other signs of meningeal irritation. Common causes include enteroviruses, such as echovirus, coxsackievirus, and mumps virus. There is no specific treatment for most viral infections of the nervous system. |
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224. Dx of viral meningitis
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CSF shows an elevated WBC count w/a lymphocytic predominance, normal or mildly elevated protein, and normal glucose.
In the early stages, a PMN predominance may be present. |
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225. Viral encephalitis
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Viral infections that involve the brain parenchyma.
Unlike typical cases of viral meningitis, the clinical manifestations of viral encephalitis are often quite severe. The meninges are often also involved, resulting in meningoencephalitis. |
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226. What is the most common cause of viral encephalitis?
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Herpes simplex type 1 (Type 2 also sometimes causes encephalitis).
The HSV has a tropism for limbic cortex. Patients often present w/bizarre psychotic behavior, confusion, lethargy, headache, fever, meningeal signs, and seizures. Focal signs such as anosmia, hemiparesis, memory loss, and aphasia may be present as well. |
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227. Other characteristics of herpes simplex encephalitis
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Also causes necrosis of unilateral or bilateral temporal and frontal structures often visible on MRI scan. Changes in EEG over one or both temporal lobes, CSF shows a mixed lymphocytic-PMN predominance, with elevated protein and normal glucose.
Untreated, it usually progresses w/in days to coma and death. Therefore, it is essential to initiate therapy promptly w/acyclovir. |
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228. Treatment of other causes of viral encephalitis
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There are a variety of other causes of viral encephalitis, but unfortunately none of these have a specific treatment. Prognosis depends on the causative agent.
In addition, postinfectious encephalitis can occur, usually several days after a viral infection, with diffuse autoimmune demyelination of the CNS. |
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229. HIV associated disorders of the nervous system
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1. AIDS dementia complex
2. HSV 3. Varicella-zoster virus 4. CMV 5. Progressive leukoencephalopathy 6. Cryptococcal meningitis 7. Toxoplasmosis 8. Primary CNS lymphoma |
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230. Cysticercosis
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Caused by ingestion of the eggs of teh pork tapeworm Taenia solium. The organism migrates thru the bloodstream to the whole body, forming multiple small cysts in the muscles, eyes and CNS.
Seizures are a common result. Other common features are headache, nausea, vomiting, lymphocytic meningitis, and focal deficits, depending on cyst location. The spinal cord can also be involved, and it can lead to hydrocephalus. |
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231. Dx and treatment of cysticercosis
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Dx by a history in appropriate populations, by typical radiologic appearance, and by antibody tests of the serum and CSF.
Sometimes, eosinophilia, parasites in the stool, and soft tissue calcifications on x-rays may be present as well. The condition is treated w/albendazole. |
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232. Murcormycosis
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Important fungal infection which occurs mainly in diabetics in the rhinocerebral form and also involves the orbital apex.
Rhinocerebral murcormycosis causes opthalmoplegia, facial numbness, visual loss, and facial weakness, with a typical violet coloration of the tips of the eyelids. Most fungal infections can be Dx via biopsy. Treatment is with amphotericin B; steroids can exacerbate fungal infections and should be avoided if a fungal infection is suspected. |
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233. Prion
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A novel protein based infection agent that has been identified in certain neurologic disorders.
They're unique in their ability to transmit diseases from one animal to another, despite the fact that they apparently do not contain DNA or RNA. Pathologically, diffuse degenereation of the brain and spinal cord occurs, with multiple vacuoles resulting in a spongiform appearance. Most common illness is Creutzfeldt-Jakob disease. |
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234. Creutzfeldt-Jakob disease
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Typical presenting features are rapidly progressive dementia, an exacerbated startle response, myoclonus, visual distortions, and ataxia.
EEG often shows periodic sharp wave complexes. Unfortunately, there is no treatment; progressive neurologic deterioration and death usually occur within 6-12 months. |
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235. Traumatic tap
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RBCs introduced into the CSF via damage to blood vessels by the spinal needle at the time of lumbar puncture.
In a traumatic tap, one WBC is introduced into the CSF for every 700 RBCs. |
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236. Left hemiparesis and left Babinski's sign, visual and tactile extinction on the left, right sided headache, and generalized fatigue
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Dx: A large, right-sided subdural hematoma
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237. Unresponsive except to painful stimuli, absent right corneal reflex, and no right arm or leg movement to pain with plantar response absent on the right and upgoing on the left.
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A thin, crescent shaped hematoma on the left side extends over a large region, consistent with an acute subdural hematoma.
This is a classic coup-contrecoup injury in which a blow to one side of the head is accompanied by deceleration injury on the opposite side of the brain as it bangs against the inner surface of the skull. |
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238. Agitation and decreased level of consciousness, left pupil fixed and dilated, right hemiplegia, right hyperreflexia, and right Babinski's sign
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Fracture of the left temporal bone causing an epidural hematoma, which caused an extensive midline shift with displacement of the entire brain to the right, compressing the left lateral ventricle. Thus, herniation likely occurred.
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239. Headaches and left hemiparesis
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Right intracranial lesion affecting corticobulbar and corticospinal tracts at or above the level of the pons.
MRI is consistent with primary brain tumor called gliobastoma multiforme, involving mainly the right hemisphere. |
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240. New onset headaches for a man in his 50's, together with a progressive neurologic deficit over a 6-month period, suggests...?
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A brain tumor, most commonly glioblastoma multiforme or metastasis. Other, less likely possibilities include infection, demyelination, multiple small hemorrhages or infarcts, or vasculitis.
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241. Duret-Bernard hemorrhage
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An irregular area of dark brown pigmentation in the center of the midbrain.
This finding is called a Duret-Bernard hemorrhage and can be seen w/severe compression of the midbrain and other brainstem areas during transtentorial herniation. |
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242. Unarousable, bilateral fixed pupils and absent eye movements, and bilateral extensor posturing
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Coma, together with absent eye movements and absent pupillary reflexes suggests severe brainstem dysfunction involving the ascending activating systems as well as CNs III, IV, and VI.
Most likely Dx is a large hemorrhage above the brainstem that could be compressing the brainstem bilaterally through downward herniation. |
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243. Headaches, nausea, and pailledema, horizontal diplopia and incomplete abduction of the left eye when looking to the left
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This patient has elevated ICP caused by hydrocephalus.
Abducen's palsy produced by mildly elevated ICP can be unilateral, and may become bilateral with more severe pressure elevations |
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244. Transependymal absorption of CSF
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On a T1- MRI, there are some regions of decreased intensity in the white matter adjacent to the frontal and occipital horns.
This represents transependymal absorption of CSF from the ventricles into the white matter and is a sign that hydrocephalus has developed relatively recently and is severe. |
